MSX-3 explained

Class:Adenosine A2A receptor antagonist
Cas Number:261705-79-7
Pubchem:10256042
Chemspiderid:8431526
Unii:72MRN83M4A
Chembl:1205720
Iupac Name:3-[8-[(''E'')-2-(3-methoxyphenyl)ethenyl]-7-methyl-2,6-dioxo-1-prop-2-ynylpurin-3-yl]propyl dihydrogen phosphate
C:21
H:23
N:4
O:7
P:1
Smiles:CN1C(=NC2=C1C(=O)N(C(=O)N2CCCOP(=O)(O)O)CC#C)/C=C/C3=CC(=CC=C3)OC
Stdinchi:1S/C21H23N4O7P/c1-4-11-25-20(26)18-19(24(21(25)27)12-6-13-32-33(28,29)30)22-17(23(18)2)10-9-15-7-5-8-16(14-15)31-3/h1,5,7-10,14H,6,11-13H2,2-3H3,(H2,28,29,30)/b10-9+
Stdinchikey:DUCGTTGSVYZHJS-MDZDMXLPSA-N

MSX-3 is a selective adenosine A2A receptor antagonist used in scientific research.[1] [2] Similarly to MSX-4, it is a water-soluble ester prodrug of MSX-2.[3] [4]

Medicinal chemistry

MSX-3, MSX-4, and MSX-2 are xanthines and are derivatives of the non-selective adenosine receptor antagonist caffeine. MSX-2 has been extensively studied due to its high affinity and selectivity for the adenosine A2A receptor, but use of MSX-2 itself has been limited by its poor water solubility.[5]

Whereas MSX-3 is a phosphate ester prodrug of MSX-2 that is suited best for intravenous administration and not for oral administration, MSX-4 is an amino acid ester (L-valine) prodrug of MSX-2 that can be orally administered.

Pharmacology

MSX-2 has 500-fold higher affinity for the adenosine A2A receptor over the adenosine A1 receptor, 580-fold higher affinity for the adenosine A2A receptor over the adenosine A2B receptor, and is inactive at the adenosine A3 receptor.[6] [7]

MSX-3 itself also showed some affinity for the adenosine receptors, but this may have just been due to degradation by phosphatases in the in vitro system.

Animal studies

MSX-3 shows pro-motivational effects in animals.[8] Specifically, although it showed no effect on its own, the drug reverses the effort-related deficits induced by the dopamine depleting agent tetrabenazine (TBZ), the dopamine D2 receptor antagonists haloperidol and eticlopride, and the proinflammatory cytokines interleukin-6 and interleukin-1β.[9] [10] [11] [12]

Conversely, it only mildly attenuates the motivational deficits induced by the dopamine D1 receptor antagonist ecopipam (SCH-39166).[13]

History

MSX-3 was first described in the scientific literature by 1998. A similar agent, MSX-4, was subsequently described by 2008.[14]

Notes and References

  1. Salamone JD, Correa M, Ferrigno S, Yang JH, Rotolo RA, Presby RE . The Psychopharmacology of Effort-Related Decision Making: Dopamine, Adenosine, and Insights into the Neurochemistry of Motivation . Pharmacological Reviews . 70 . 4 . 747–762 . October 2018 . 30209181 . 6169368 . 10.1124/pr.117.015107 .
  2. Müller CE . Prodrug approaches for enhancing the bioavailability of drugs with low solubility . Chemistry & Biodiversity . 6 . 11 . 2071–2083 . November 2009 . 19937841 . 10.1002/cbdv.200900114 .
  3. Müller CE, Sauer R, Maurinsh Y, Huertas R, Fülle F, Klotz KN, Nagel J, Hauber W . A2A-selective adenosine receptor antagonists: Development of water-soluble prodrugs and a new tritiated radioligand . Drug Development Research . 45 . 3–4 . 1998 . 0272-4391 . 10.1002/(SICI)1098-2299(199811/12)45:3/4<190::AID-DDR16>3.0.CO;2-A . 190–197.
  4. Hauber W, Nagel J, Sauer R, Müller CE . Motor effects induced by a blockade of adenosine A2A receptors in the caudate-putamen . NeuroReport . 9 . 8 . 1803–1806 . June 1998 . 9665604 . 10.1097/00001756-199806010-00024 .
  5. de Lera Ruiz M, Lim YH, Zheng J . Adenosine A2A receptor as a drug discovery target . Journal of Medicinal Chemistry . 57 . 9 . 3623–3650 . May 2014 . 24164628 . 10.1021/jm4011669 .
  6. Yuzlenko O, Kieć-Kononowicz K . Potent adenosine A1 and A2A receptors antagonists: recent developments . Current Medicinal Chemistry . 13 . 30 . 3609–3625 . 2006 . 17168726 . 10.2174/092986706779026093 .
  7. Book: Khayat MT, Hanif A, Geldenhuys WJ, Nayeem MA . Adenosine Receptors and Drug Discovery in the Cardiovascular System . 16–64 . Choudhary MI . Frontiers in Cardiovascular Drug Discovery: Volume 4 . Amazon Digital Services LLC - Kdp . 2019 . 978-1-68108-400-8 . https://books.google.com/books?id=R6SXDwAAQBAJ&pg=PA16 . 23 September 2024.
  8. López-Cruz L, Salamone JD, Correa M . Caffeine and Selective Adenosine Receptor Antagonists as New Therapeutic Tools for the Motivational Symptoms of Depression . Frontiers in Pharmacology . 9 . 526 . 2018 . 29910727 . 5992708 . 10.3389/fphar.2018.00526 . free .
  9. Salamone JD, Correa M, Farrar AM, Nunes EJ, Collins LE . Role of dopamine–adenosine interactions in the brain circuitry regulating effort-related decision making: insights into pathological aspects of motivation . Future Neurology . 5 . 3 . 5 May 2010 . 1479-6708 . 10.2217/fnl.10.19 . 377–392. 10234/35900 . free .
  10. Mott AM, Nunes EJ, Collins LE, Port RG, Sink KS, Hockemeyer J, Müller CE, Salamone JD . The adenosine A2A antagonist MSX-3 reverses the effects of the dopamine antagonist haloperidol on effort-related decision making in a T-maze cost/benefit procedure . Psychopharmacology . 204 . 1 . 103–112 . May 2009 . 19132351 . 2875244 . 10.1007/s00213-008-1441-z .
  11. Nunes EJ, Randall PA, Estrada A, Epling B, Hart EE, Lee CA, Baqi Y, Müller CE, Correa M, Salamone JD . Effort-related motivational effects of the pro-inflammatory cytokine interleukin 1-beta: studies with the concurrent fixed ratio 5/ chow feeding choice task . Psychopharmacology . 231 . 4 . 727–736 . February 2014 . 24136220 . 4468782 . 10.1007/s00213-013-3285-4 .
  12. Yohn SE, Arif Y, Haley A, Tripodi G, Baqi Y, Müller CE, Miguel NS, Correa M, Salamone JD . Effort-related motivational effects of the pro-inflammatory cytokine interleukin-6: pharmacological and neurochemical characterization . Psychopharmacology . 233 . 19–20 . 3575–3586 . October 2016 . 27497935 . 10.1007/s00213-016-4392-9 .
  13. Worden LT, Shahriari M, Farrar AM, Sink KS, Hockemeyer J, Müller CE, Salamone JD . The adenosine A2A antagonist MSX-3 reverses the effort-related effects of dopamine blockade: differential interaction with D1 and D2 family antagonists . Psychopharmacology . 203 . 3 . 489–499 . April 2009 . 19048234 . 2875246 . 10.1007/s00213-008-1396-0 .
  14. Vollmann K, Qurishi R, Hockemeyer J, Müller CE . Synthesis and properties of a new water-soluble prodrug of the adenosine A 2A receptor antagonist MSX-2 . Molecules . 13 . 2 . 348–359 . February 2008 . 18305423 . 6244838 . 10.3390/molecules13020348 . free .

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